PROJECT SUMMARY ABSTRACT CMA: Marker-assisted prevention and risk stratification (MAPRS): Mucin signatures and their molecular imaging for the early detection of colorectal cancer Herein, a group of collaborative merit review applications (CMA) aim to advance precision management of cancers, especially focusing on marker-assisted prevention and risk stratification (MAPRS) of colorectal cancers (CRCs), which is the third major cancer in the USA and accounts for 9.5% of all cancers among Veterans. While screening colonoscopy has emerged as perhaps the most effective lifesaving intervention against CRC to date, their successes have been limited by ease-of-use and downward cost pressures. Also, despite high R0 resection rates in patients with CRC, local and distant recurrence is still a significant problem and has been cited as high as 40 per cent. The proposed CMAs aim to address these limitations and to significantly disrupt CRC prevention, detection, risk stratification and precision treatment by advancing MAPRS. The projects include the followings. CMA1 aims to develop artificial intelligence enhanced endoscopy for colorectal cancer prevention. CMA2 plans to examine mucin-based markers for improved endoscopic detection, resection, histological classification and surveillance of pre-malignant colonic polyp (sessile serrated adenoma/polyps and adenoma) and examine their clinical utility as an adjunct to screening colonoscopy. CMA3 proposes to validate tissue and blood-based combinatorial biomarker panels, derived from functional pathway-specific studies, to improve the early detection of colon cancer and stratify populations according to their risk for developing CRC. Finally, CMA4 plans to examine the genomic and/or cellomic drug response profiling using patients? tumor discards and develop a tumor-on-chip platform toward an evidence- based precision treatment strategy for CRCs. These CMRs are linked both intrinsically among each other and extrinsically with VA colorectal cancer cellgenomics consortium (VA4C) to maximize synergy and ensure success. Rationale: With a lifetime development risk of 5%, CRC is the third-most common cancer and the second major cause of cancer-related deaths. Colonoscopy polypectomy during screening have significantly reduced both incidence and overall mortality. Further, even after widespread use of screening colonoscopy, there is an age-adjusted incidence of and mortality from prevalent, right-sided CRCs. Major proportion of these tumors emerge from sessile serrated adenoma/polyps (SSA/Ps) that have gone undetected during initial colonoscopy. Furthermore, only 40% of CRCs are diagnosed at early stage, in part due to lack of compliance and to low sensitivity and specificity of the more common tests, including fecal occult blood tests and the insidious (asymptomatic) nature of localized disease. Our preliminary data suggest altered expression of various mucins during CRC progression, characterized by aberrant localization and glycosylation and differential expression. Based on preliminary studies and the identified gaps in diagnosis, we hypothesize that a serum based combinatorial biomarker panel based on altered expression and glycosylation of mucins will serve as a powerful adjunct to colonoscopy and will improve surveillance efficiency, endoscopy based imaging, and adherence to physician recommendations by more accurate lesion classification for risk prediction of future malignancy. Clinical implications: This project focuses on accurate risk stratification (via quick far field blood test) and proposes an adjunct approach (fluorescent mucin antibody visualization of polyps in high-risk patients) for identifying malignant polyps, the hidden culprits for 15-30% colon cancer. Furthermore, tumor-specific antibodies conjugated to near infrared (NIR) fluorophores that label CRC and liver metastases will enable successful fluorescence-guided surgery (FGS). Due to the utilization of unique imaging technology for early and accurate detection of premalignant polyps and CRC, the present project and can significantly affect management of CRC patients.